DESCRIPTION: (Applicant's Abstract) There is strong evidence from animal studies with some support from human studies that 5HT systems are involved in cocaine use. The proposed research project is designed to investigate whether a group of cocaine dependent (CD) individuals display 5HT dysfunction as indicated by hormonal responses to meta-chlorophenylpiperazine (m-CPP) and platelet tritiated paroxetine binding and whether this group differs from other CD individuals in polymorphisms in genes for Serotonin Transporter (SERT) and tryptophan hydroxylase (TrPH) and clinical measures of impulsivity, aggression, craving and compulsive drug use. Furthermore, the project plans to determine if this particular group has a different outcome to treatment than other CD patients. Two hundred carefully screened subjects suffering from CD and volunteering for the study and a matched group of controls will be studied. After undergoing a comprehensive assessment and after 3 weeks of abstinence from cocaine, the subjects will undergo the m-CPP challenge in a double blind randomized design. Along with the hormonal responses to m-CPP, platelet tritiated paroxetine binding and polymorphisms in the genes for SERT and TrPH will be studied. The subjects will participate in 3 month intensive outpatient program and will be assessed on measures of outcome at the end of 3 months and after 6 months follow up. It is hypothesized that a group of CD subjects will display central 5HT dysfunction as indicated by a blunted hormonal response to m-CPP and reduced platelet tritiated paroxetine binding compared to other CD subjects and controls. Furthermore, it is also expected that this particular group of CD subjects will display polymorphisms in genes for SERT and TrPH and higher impulsivity, hostility, compulsive drug use and cocaine craving compared to the rest of CD subjects and controls. Finally, it is expected that this group will show a poorer outcome to treatment compared to other CD subjects.